Abstract

Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF) on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT) mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs), we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-naïve individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 - A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F - were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMs will be important for monitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen.

Figures

Prevalence of nucleoside RT inhibitor (NRTI)-associated tenofovir disoproxil fumarate (TDF)-regimen associated mutations (TRAMs) in 2,873 individuals with virological failure (VF) on a TDF-containing 1st-line regimen (a); in 5,805 individuals with VF on a thymidine analog-containing 1st-line regimen (b); and in 50,803 antiretroviral (ARV)-naive individuals (c). NRTI TRAMs that were significantly more common in individuals receiving a TDF-containing regimen compared to in individuals receiving a thymidine analog-containing regimen are shown in blue. NRTI TRAMs that were significantly more common in individuals receiving a thymidine analog-containing regimen compared to in individuals receiving a TDF-containing regimen are shown in brown.

Prevalence of non-nucleoside RT inhibitor (NRTI)-associated tenofovir disoproxil fumarate (TDF)-regimen associated mutations (TRAMs) in 2,873 individuals with virological failure (VF) on a TDF-containing 1st-line regimen (a); in 5,805 individuals with VF on a thymidine analog-containing 1st-line regimen (b); and in 50,803 antiretroviral (ARV)-naive individuals (c). NNRTI TRAMs that were significantly more common in individuals receiving a TDF-containing regimen compared to in individuals receiving a thymidine analog-containing regimen are shown in blue. NNRTI TRAMs that were significantly more common in individuals receiving a thymidine analog-containing regimen compared to in individuals receiving a TDF-containing regimen are shown in brown.

Covariation patterns of nucleoside RT inhibitor (NRTI)-associated tenofovir disoproxil fumarate (TDF)-regimen associated mutations (TRAMs) in a network created from the adjacency matrix of phi correlation coefficients for each pair of NRTI TRAMs. Each edge in the network represents a strongly significant correlation (phi ≥ 0.1 and an adjusted p